2-Thia-dibenzoazulenes as inhibitors of tumour necrosis factor production and intermediates for the preparation thereof

ABSTRACT

The present invention relates to compounds of 2-thia-dibenzoazulene class, to their pharmacologically acceptable salts and solvates, to processes and intermediates for the preparation thereof as well as to their antiinflammatory effects, especially to the inhibition of tumour necrosis factor-α(TNF-α) production and the inhibition of interleukin-1 (IL-1) production as well as to their analgetic action.

TECHNICAL FIELD

The present invention relates to compounds of 2-thia-dibenzoazuleneclass, to their pharmacologically acceptable salts and solvates, toprocesses and intermediates for the preparation thereof as well as totheir antiinflammatory effects, especially to the inhibition of tumournecrosis factor-α (TNF-α) production and the inhibition of interleukin-1(IL-1) production as well as to their analgetic action.

PRIOR ART

Hitherto, in the literature derivatives of 1-thia-dibenzoazulenessubstituted in 2-position with methyl, methyl-ketone, nitro group orwith carboxylic group derivatives (Cagniant P G, C. R. Hebd. SceancesAcad. Sci., 1976, 283:683-686) have been described. Some1,3-diaza-dibenzoazulene derivatives and salts thereof are known as anovel class of compounds having an antiinflammatory action (U.S. Pat.No. 3,711,489, U.S. Pat. No. 4,198,421 and CA 967,573).1-Thia-dibenzoazulene derivatives having alkyloxy substituents in2-position (WO 01/878990) also possess strong antiinflammatory action.However, according to our knowledge and to available literature data,compounds of 2-thia-dibenzoazulene structure in general have hithertonot been known and, thus, neither have been derivatives derived fromthis structure or their antiinflammatory action as inhibitors of TNF-αsecretion and inhibitors of IL-1 secretion or their analgetic action.

In 1975 TNF-α was defined as a serum factor induced by endotoxin andcausing tumour necrosis in vitro and in vivo (Carswell E A et al., Proc.Natl. Acad. Sci. USA., 1975, 72:3666-3670). Besides an antitumouraction, TNF-α also possesses numerous other biological actions importantin the homeostasis of an organism and in pathophysiological conditions.The main sources of TNF-α are monocytes-macrophages, T-lymphocytes andmastocytes.

The discovery that anti-TNF-α antibodies (cA2) have an action intreating patients with rheumatoid arthritis (RA) (Elliott M et al.,Lancet, 1994, 344:1105-1110) led to an increased interest in findingnovel TNF-α inhibitors as possible potent drugs for RA. Rheumatoidarthritis is an autoimmune chronic inflammatory disease characterized byirreversible pathological changes in the joints. Besides in RA, TNF-αantagonists may also be used in numerous pathological conditions anddiseases such as spondylitis, osteoarthritis, gout and other arthriticconditions, sepsis, septic shock, toxic shock syndrom, atopicdermatitis, contact dermatitis, psoriasis, glomerulonephritis, lupuserythematosus, scleroderma, asthma, cachexia, chronic obstructive lungdisease, congestive cardiac arrest, insulin resistance, lung fibrosis,multiple sclerosis, Crohn's disease, ulcerative colitis, viralinfections and AIDS.

Evidence for the biological importance of TNF-α was obtained by in vivoexperiments in mice, in which mice gens for TNF-α or its receptor wereinactivated. Such animals are resistant to collagen-induced arthritis(Mori L et al., J. Immunol., 1996, 157:3178-3182) and toendotoxin-caused shock (Pfeffer K et al., Cell, 1993, 73:457-467). Inanimal experiments where TNF-α level was increased, a chronicinflammatory polyarthritis occured (Georgopoulos S et al., J. Inflamm.,1996, 46:86-97; Keffer J et al., EMBO J., 1991, 10:4025-4031) and itspathological picture was alleviated by inhibitors of TNF-α production.The treatment of such inflammatory and pathological conditions usuallyincludes the application of non-steroid antiinflammatory drugs and, inmore severe cases, gold salts, D-penicillinamine or methotrexate areadministered. Said drugs act symptomatically, but they do not stop thepathological process. Novel approaches in the therapy of rheumatoidarthritis are based upon drugs such as tenidap, leflunomide,cyclosporin, FK-506 and upon biomolecules neutralizing the TNF-α action.At present there are commercially available etanercept (Enbrel,Immunex/Wyeth), a fusion protein of the soluble TNF-α receptor, andinfliximab (Remicade, Centocor), a chimeric monoclonal human and mouseantibody. Besides in RA therapy, etanercept and infliximab are alsoregistered for the therapy of Crohn's disease (Exp. Opin. Invest. Drugs,2000, 9:103).

In RA therapy, besides inhibition of TNF-α secretion, also theinhibition of IL-1 secretion is very important since IL-1 is animportant cytokin in cell regulation and immunoregulation as well as inpathophysiological conditions such as inflammation (Dinarello C A etal., Rev. Infect. Disease, 1984, 6:51). Well-known biological activitiesof IL-1 are: activation of T-cells, induction of elevated temperature,stimulation of secretion of prostaglandine or collagenase, chemotaxia ofneutrophils and reduction of iron level in plasma (Dinarello C A, J.Clinical Immunology, 1985, 5:287). Two receptors to which IL-1 may bindare well-known: IL-1RI and IL-1RII. Whereas IL-1RI transfers a signalintracellularly, IL-1RII is situated on the cell surface and does nottransfer a signal inside the cell. Since IL1-RII binds IL-1 as well asIL1-RI, it may act as a negative regulator of IL-1 action. Besides thismechanism of signal transfer regulation, another natural antagonist ofIL-1 receptor (IL-1ra) is present in cells. This protein binds to IL-1RIbut does not transfer any signal. However, its potency in stopping thesignal transfer is not high and its concentration has to be 500 timeshigher than that of IL-1 in order to achieve a break in the signaltransfer. Recombinant human IL-1ra (Amgen) was clinically tested(Bresnihan B et al., Arthrit. Rheum., 1996, 39:73) and the obtainedresults indicated an improvement of the clinical picture in 472 RApatients over an placebo. These results indicate the importance of theinhibition of IL-1 action in treating diseases such as RA where IL-1production is disturbed. Since there exists a synergistic action ofTNF-α and IL-1, 2-thia-dibenzoazulenes may be used in treatingconditions and diseases related to an enhanced secretion of TNF-α andIL-1.

SOLUTION OF TECHNICAL PROBLEM

The present invention relates to 2-thia-dibenzoazulenes of the formula I

wherein

-   -   X may be CH₂ or a hetero atom such as O, S, S(═O), S(═O)₂, or        NR^(a), wherein R^(a) is hydrogen or a protecting group;    -   Y and Z independently from each other denote one or more        identical or different substituents linked to any available        carbon atom, and may be halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl,        C₂-C₄ alkinyl, trifluoromethyl, halo-C₁-C₄ alkyl, hydroxy, C₁-C₄        alkoxy, trifluoromethoxy, C₁-C₄ alkanoyl, amino, amino-C₁-C₄        alkyl, C₁-C₄ alkylamino, N—(C₁-C₄-alkyl)amino,        N,N-di(C₁-C₄-alkyl)amino, thiol, C₁-C₄ alkylthio, sulfonyl,        C₁-C₄ alkylsulfonyl, sulfinyl, C₁-C₄ alkylsulfinyl, carboxy,        C₁-C₄ alkoxycarbonyl, cyano, nitro;    -   R¹ may be hydrogen, halogen, an optionally substituted C₁-C₇        alkyl or C₂-C₇ alkenyl, C₂-C₇ alkinyl, an optionally substituted        aryl or heteroaryl and a heterocycle, hydroxy, hydroxy-C₂-C₇        alkenyl, hydroxy-C₂-C₇ alkinyl, C₁-C₇ alkoxy, thiol, thio-C₂-C₇        alkenyl, thio-C₂-C₇ alkinyl, C₁-C₇ alkylthio, amino, N—(C₁-C₇        alkyl)amino, N,N-di-(C₁-C₇ alkyl)amino, C₁-C₇ alkylamino,        amino-C₂-C₇ alkenyl, amino-C₂-C₇ alkinyl, amino-C₁-C₇ alkoxy,        C₁-C₇ alkanoyl, aroyl, oxo-C₁-C₇ alkyl, C₁-C₇ alkanoyloxy,        carboxy, an optionally substituted C₁-C₇ alkyloxycarbonyl or        aryloxycarbonyl, carbamoyl, N—(C₁-C₇-alkyl)carbamoyl,        N,N-di(C₁-C₇-alkyl)carbamoyl, cyano, cyano-C₁-C₇ alkyl,        sulfonyl, C₁-C₇ alkylsulfonyl, sulfinyl, C₁-C₇ alkylsulfinyl,        nitro, or a substituent of the formula II        wherein    -   R³ and R⁴ simultaneously or independently from each other may be        hydrogen, C₁-C₄alkyl, aryl or together with N have the meaning        of an optionally substituted heterocycle or heteroaryl;    -   m and n represent an integer from 0 to 3;    -   Q₁ and Q₂ represent, independently from each other, oxygen,        sulfur or groups:        wherein the substituents    -   y₁ and y₂ independently from each other may be hydrogen,        halogen, an optionally substituted C₁-C₄ alkyl or aryl, hydroxy,        C₁-C₄ alkoxy, C₁-C₄ alkanoyl, thiol, C₁-C₄ alkylthio, sulfonyl,        C₁-C₄ alkylsulfonyl, sulfinyl, C₁-C₄ alkylsulfinyl, cyano, nitro        or together form carbonyl or imino group;    -   R² may be hydrogen, carboxy or alkyloxycarbonyl;        as well as to pharmacologically acceptable salts and solvates        thereof.

The term “halo”, “hal” or “halogen” relates to a halogen atom which maybe fluorine, chlorine, bromine or iodine.

The term “alkyl” relates to alkyl groups with the meaning of alkaneswherefrom radicals are derived, which radicals may be straight, branchedor cyclic or a combination of straight and cyclic ones and branched andcyclic ones. The preferred straight or branched alkyls are e.g. methyl,ethyl, propyl, isopropyl, butyl, sec-butyl and tert-butyl. The preferredcyclic alkyls are e.g. cyclopentyl or cyclohexyl.

The term “haloalkyl” relates to alkyl groups which must be substitutedwith at least one halogen atom. The most frequent haloalkyls are e.g.chloromethyl, dichloromethyl, trifluoromethyl or 1,2-dichloropropyl.

The term “alkenyl” relates to alkenyl groups having the meaning ofhydrocarbon radicals, which may be straight, branched or cyclic or are acombination of straight and cyclic ones or branched and cyclic ones, buthaving at least one carbon-carbon double bond. The most frequentalkenyls are ethenyl, propenyl, butenyl or cyclohexenyl.

The term “alkinyl” relates to alkinyl groups having the meaning ofhydrocarbon radicals, which are straight or branched and contain atleast one and at most two carbon-carbon triple bonds. The most frequentalkinyls are e.g. ethinyl, propinyl or butinyl.

The term “alkoxy” relates to straight or branched chains of alkoxygroup. Examples of such groups are methoxy, propoxy, prop-2-oxy, butoxy,but-2-oxy or methylprop-2-oxy.

The term “aryl” relates to groups having the meaning of an aromaticring, e.g. phenyl, as well as to fused aromatic rings. Aryl contains onering with at least 6 carbon atoms or two rings with totally 10 carbonatoms and with alternating double (resonant) bonds between carbon atoms.The most frequently used aryls are e.g. phenyl or naphthyl. In general,aryl groups may be linked to the rest of the molecule by any availablecarbon atom via a direct bond or via a C₁-C₄ alkylene group such asmethylene or ethylene.

The term “heteroaryl” relates to groups having the meaning of aromaticand partially aromatic groups of a monocyclic or bicyclic ring with 4 to12 carbon atoms, at least one of them being a hetero atom such as O, Sor N, and the available nitrogen atom or carbon atom is the binding siteof the group to the rest of the molecule either via a direct bond or viaa C₁-C₄ alkylene group defined earlier. Examples of this type arethiophenyl, pyrrolyl, imidazolyl, pyridinyl, oxazolyl, thiazolyl,pyrazolyl, tetrazolyl, pirimidinyl, pyrazinyl, quinolinyl or triazinyl.

The term “heterocycle” relates to five-member or six-member, fullysaturated or partly unsaturated heterocyclic groups containing at leastone hetero atom such as O, S or N, and the available nitrogen atom orcarbon atom is the binding site of the group to the rest of the moleculeeither via a direct bond or via a C₁-C₄ alkylene group defined earlier.The most frequent examples are morpholinyl, piperidinyl, piperazinyl,pyrrolidinyl, pirazinyl or imidazolyl.

The term “alkanoyl” group relates to straight chains of acyl group suchas formyl, acetyl or propanoyl.

The term “aroyl” group relates to aromatic acyl groups such as benzoyl.

The term “optionally substituted alkyl” relates to alkyl groups whichmay be optionally additionally substituted with one, two, three or moresubstituents. Such substituents may be halogen atom (preferably fluorineor chlorine), hydroxy, C₁-C₄ alkoxy (preferably metboxy or ethoxy),thiol, C₁-C₄ alkylthio (preferably methylthio or ethylthio), amino,N—(C₁-C₄) alkylamino (preferably N-methylamino or N-ethylamino),N,N-di(C₁-C₄-alkyl)-amino (preferably dimethylamino or diethylamino),sulfonyl, C₁-C₄ alkylsulfonyl (preferably methylsulfonyl orethylsulfonyl), sulfinyl, C₁-C₄ alkylsulfinyl (preferablymethylsulfinyl).

The term “optionally substituted alkenyl” relates to alkenyl groupsoptionally additionally substituted with one, two or three halogenatoms. Such substituents may be e.g. 2-chloroethenyl,1,2-dichloroethenyl or 2-bromo-propene-1-yl.

The term “optionally substituted aryl, heteroaryl or heterocycle”relates to aryl, heteroaryl or heterocyclic groups which may beoptionally additionally substituted with one or two substituents. Thesubstituents may be halogen (preferably chlorine or fluorine), C₁-C₄alkyl (preferably methyl, ethyl or isopropyl), cyano, nitro, hydroxy,C₁-C₄ alkoxy (preferably methoxy or ethoxy), thiol, C₁-C₄ alkylthio(preferably methylthio or ethylthio), amino, N—(C₁-C₄) alkylamino(preferably N-methylamino or N-ethylamino), N,N-di(C₁-C₄-alkyl)-amino(preferably N,N-dimethylamino or N,N-diethylamino), sulfonyl, C₁-C₄alkylsulfonyl (preferably methylsulfonyl or ethylsulfonyl), sulfinyl,C₁-C₄ alkylsulfinyl (preferably methylsulfinyl).

When X has the meaning of NR^(a) and R^(a) has the meaning of aprotecting group, then R^(a) relates to groups such as alkyl (preferablymethyl or ethyl), alkanoyl (preferably acetyl), alkoxycarbonyl(preferably methoxycarbonyl or tert-butoxycarbonyl), arylmethoxycarbonyl(preferably benzyloxycarbonyl), aroyl (preferably benzoyl), arylalkyl(preferably benzyl), alkylsilyl (preferably trimethylsilyl) oralkylsilylalkoxyalkyl (preferably trimethylsilylethoxymethyl).

When R³ and R⁴ together with N have the meaning of heteroaryl orheterocycle, this means that such heteroaryls or heterocycles have atleast one carbon atom replaced by a nitrogen atom through which thegroups are linked to the rest of the molecule. Examples of such groupsare morpholine-4-yl, piperidine-1-yl, pyrrolidine-1-yl, imidazole-1-ylor piperazine-1-yl.

The term “pharmaceutically suitable salts” relates to salts of thecompounds of the formula I and include e.g. salts with C₁-C₄alkylhalides (preferably methyl bromide, methyl chloride) (quaternaryammonium salts), with inorganic acids (hydrochloric, hydrobromic,phosphoric, metaphosphoric, nitric or sulfuric acids) or with organicacids (tartaric, acetic, citric, maleic, lactic, fumaric, benzoic,succinic, methane sulfonic or p-toluene sulfonic acids).

Some compounds of the formula I may form salts with organic or inorganicacids or bases and these are also included in the present invention.

Solvates (most frequently hydrates) which may form compounds of theformula I or salts thereof are also an object of the present invention.

Depending upon the nature of particular substituents, the compounds ofthe formula I may have geometric isomers and one or more chiral centresso that there can exist enantiomers or diastereoisomers. The presentinvention also relates to such isomers and mixtures thereof, includingracemates.

The present invention also relates to all possible tautomeric forms ofparticular compounds of the formula I.

A further object of the present invention relates to the preparation ofcompounds of the formula I according to processes comprising:

-   -   a) for compounds of the formula I, wherein R¹ and R² represent,        independently from each other, carboxyl group, C₁-C₆        alkyloxycarbonyl, aryloxycarbonyl or arylalkyloxycarbonyl,        -   a cyclisation of α-diketones of the formula III:            with compounds of the formula IV:    -   b) for compounds of the formula I, wherein Q₁ has a meaning of        —O—, a reaction of alcohols of the formula V:        with compounds of formula VI:        wherein R⁵ has the meaning of a leaving group;    -   c) for the compounds of the formula I, wherein Q₁ has a meaning        of —O—, —NH—, —S— or —C≡C—,        -   a reaction of the compounds of the formula Va:            wherein L¹ has the meaning of a leaving group,    -   with compounds of the formula VIa:    -   d) for the compounds of the formula I, wherein Q₁ has a meaning        of —O—, —NH— or —S—,        -   a reaction of the compounds of the formula Vb:            with the compounds of the formula VI, wherein R⁵ has the            meaning of a leaving group;    -   e) for the compounds of the formula I, wherein Q₁ has the        meaning of —C═C—, a reaction of the compounds of the formula Vb,        wherein Q₁ has the meaning of carbonyl, with phosphorous ylides.        Preparation Methods:

a) Cyclization of α-diketones of the formula III and of compounds of theformula IV, wherein R¹ and R² simultaneously or independently from eachother represent C₁-C₆-alkyloxycarbonyl, aryloxycarbonyl orarylalkyloxycarbonyl, is carried out by methods disclosed for thepreparation of analogous compounds (Chadwick D J et al., J Chem. Soc.Perkin Trans. 1, 1972, 2079-81). The reaction of cyclization is carriedout in alcohols (most frequently in tert-butanol) in the presence ofalcoholates (preferably potassium tert-butylate).

The starting compounds for this reaction are already known or they areprepared by methods described for the preparation of analogouscompounds: for α-diketones of formula III in e.g. Leonard N. J. et al.,J. Am. Chem. Soc., 1955, 77:5078, U.S. Pat. No. 3,711,489 or LombardinoJ. G, J. Heterocyclic Chem., 1974, 11:17-21; or for thioethers offormula IV e.g. in Overberger C. G. et al., J. Am. Chem. Soc., 1950,72:4958-61. The so obtained compounds may be purified, isolated andcharacterized or may be subjected to further transformation withoutisolation.

b) The compounds of the formula I according to the present process maybe prepared by reaction of alcohols of the formula V and compounds ofthe formula VI, wherein R⁵ has the meaning of a leaving group, which maybe a halogen atom (most frequently bromine, iodine or chlorine) orsulfonyloxy group (most frequently trifluoromethylsulfonyloxy orp-toluenesulfonyloxy). The condensation reaction may be carried outaccording to methods disclosed for the preparation of analogouscompounds (Menozzi G et al., J. Heterocyclic Chem., 1997, 34:963-968 orWO 01/87890). The reaction is carried out at a temperature from 20° C.to 100° C. during 1 to 24 hours in a two-phase system (preferably with50% NaOH/toluene) in the presence of a phase transfer catalyst(preferably benzyl triethyl ammonium chloride, benzyl triethyl ammoniumbromide, cetyl trimethyl bromide). After the treatment of the reactionmixture, the products formed are isolated by recrystallization orchromatography on a silica gel column.

The starting compounds for the preparation of alcohols of the formula Vare compounds of the formula I, wherein R¹ and R² independently fromeach other have the meaning of carboxyl or ester group(ethyloxycarbonyl, methyloxycarbonyl), which by decarboxylation givecompounds of the formula I, wherein R² has the meaning of hydrogen andR¹ has the meaning of an ester group, which by reduction yield alcoholsof the formula V. Decarboxylation is carried out by pyrolysis at250-300° C. in the presence of metals, preferably copper. The reductionreaction is carried out by the use of metal hydrides such as lithiumaluminum hydride or sodium borohydride. Further, the alcohols of theformula V may be prepared by hydrolysis of the corresponding esters (inalkaline or acidic mediums).

The starting compounds of the formula VI are already known or areprepared according to methods disclosed for the preparation of analogouscompounds.

c) Compounds of the formula I may be prepared according to the presentprocess by reacting compounds of the formula Va, wherein L¹ has themeaning of a leaving group defined earlier for R⁵, and compounds of theformula VIa, wherein Q₁ has the meaning of oxygen, nitrogen, sulfur or—C≡C—. The most suitable condensation reactions are reactions ofnucleophilic substitution on a saturated carbon atom as disclosed in theliterature.

The starting compounds of the formula Va (most frequently halides) maybe obtained by halogenation (e.g. bromination or chlorination) ofalcohols of the formula V with the usual halogenating agents (e.g.hydrobromic acid, PBr₃, SOCl₂ or PCl₅) by processes as disclosed in theliterature. The obtained compounds may be isolated or may be usedwithout isolation as suitable intermediates for the preparation of thecompounds of the formula I.

The starting compounds of the formula VIa are already known or areprepared according to methods disclosed for the preparation of analogouscompounds.

d) The compounds of the formula I, wherein Q₁ has the meaning of ahetero atom —O—, —NH— or —S—, may be prepared by the condensation of thecompounds of the formula Vb and of compounds of the formula VI, whereinR⁵ has the meaning of a leaving group as defined earlier. The reactionmay be carried out at reaction conditions disclosed in the method b) orat conditions of the nucleophilic substitution reactions disclosed inthe literature. The starting alcohols, amines and thiols may be obtainedby a reaction of water, ammonia or hydrogen sulfide with compounds Vaaccording to processes disclosed in the literature.

e) The alcohols of the structure V may be oxidized to correspondingcompounds of the formula Vb, wherein Q₁ has the meaning of carbonyl,which may further, by reaction with corresponding ylide reagents, resultin a prolongation of the chain and in the formation of an alkenylsubstituent with carbonyl or ester groups as disclosed in HR patentapplication No.20000310.

Besides the above-mentioned reactions, the compounds of the formula Imay be prepared by transforming other compounds of the formula I and itis to be understood that the present invention also comprises suchcompounds and processes. A special example of a change of a functionalgroup is the reaction of the aldehyde group with chosen phosphorousylides resulting in a prolongation of the chain and the formation of analkenyl substituent with carbonyl or ester groups as disclosed in HRpatent application No. 20000310. These reactions are carried out insolvents such as benzene, toluene or hexane at elevated temperature(most frequently at boiling temperature).

By reacting the compounds of the formula Va with 1-alkyne in an alkalinemedium (such as sodium amide in ammonia), compounds of the formula I,wherein Q₁ is —C≡C—, are obtained. The reaction conditions of thisprocess are disclosed in the literature. At similar reaction conditions(nucleophilic substitution) various ether, thioether or aminederivatives may be prepared.

The formylation of the compounds of the formula I by processes such ase.g. Vilsmeier acylation or reaction of n-BuLi and dimethylformamide isa further general example of a transformation. The reaction conditionsof these processes are well-known in the literature.

By hydrolysis of the compounds of the formula I having nitrile, amide orester groups, there may be prepared compounds with a carboxyl group,which are suitable intermediates for the preparation of other compoundswith novel functional groups such as e.g. esters, amides, halides,anhydrides, alcohols or amines.

Oxidation or reduction reactions are a further possibility of the changeof substituents in the compounds of the formula I. The most frequentlyused oxidation agents are peroxides (hydrogen peroxide,m-chloroperbenzoic acid or benzoyl peroxide) or permanganate, chromateor perchlorate ions. Thus e.g. by the oxidation of an alcohol group bypyridinyl dichromate or pyridinyl chlorochromate, an aldehyde group isformed, which group may be converted to a carboxyl group by furtheroxidation. By oxidation of the compounds of the formula I, wherein R¹has the meaning of alkyl, with lead tetraacetate in acetic acid or withN-bromosuccinimide using a catalytic amount of benzoyl peroxide, acorresponding carbonyl derivative is obtained.

By a selective oxidation of alkylthio group, alkylsulfinyl oralkylsulfonyl groups may be prepared.

By the reduction of the compounds with a nitro group, the preparation ofamino compounds is made possible. The reaction is carried out underusual conditions of catalytic hydrogenation or electrochemically. Bycatalytic hydrogenation using palladium on carbon, alkenyl substituentsmay be converted to alkyl ones or the nitrite group can be converted toaminoalkyl.

Various substituents of the aromatic structure in the compounds of theformula I may be introduced by standard substitution reactions or byusual changes of individual functional groups. Examples of suchreactions are aromatic substitutions, alkylations, halogenation,hydroxylation as well as oxidation or reduction of substituents.Reagents and reaction conditions are known from the literature. Thuse.g. by aromatic substitution a nitro group is introduced in thepresence of concentrated nitric acid and sulfuric acid. By using acylhalides or alkyl halides, the introduction of an acyl group or an alkylgroup is made possible. The reaction is carried out in the presence ofLewis acids such as aluminum- or iron-trichloride in conditions ofFriedel-Crafts reaction. By the reduction of the nitro group, an aminogroup is obtained, which is by a diazotizing reaction converted to asuitable starting group, which may be replaced with one of the followinggroups: H, CN, OH, Hal.

In order to prevent undesired interaction in chemical reactions, it isoften necessary to protect certain groups such as e.g. hydroxy, amino,thio or carboxy. For this purpose a great number of protecting groupsmay be used [Green T W, Wuts P G H, Protective Groups in OrganicSynthesis, John Wiley and Sons, 1999] and the choice, use andelimination thereof are conventional methods in chemical synthesis.

A convenient protection for amino or alkylamino groups are groups suchas e.g. alkanoyl (acetyl), alkoxycarbonyl (methoxycarbonyl,ethoxycarbonyl or tert-butoxycarbonyl); arylmethoxycarbonyl(benzyloxycarbonyl), aroyl (benzoyl) or alkylsilyl (trimethylsilyl ortrimethylsilylethoxymethyl) groups. The conditions of removing aprotecting group depend upon the choice and the characteristics of thisgroup. Thus e.g. acyl groups such as alkanoyl, alkoxycarbonyl or aroylmay be eliminated by hydrolysis in the presence of a base (sodiumhydroxide or potassium hydroxide), tert-butoxycarbonyl or alkylsilyl(trimethylsilyl) may be eliminated by treatment with a suitable acid(hydrochloric, sulfuric, phosphoric or trifluoroacetic acid), whereasarylmethoxycarbonyl group (benzyloxycarbonyl) may be eliminated byhydrogenation using a catalyst such as palladium on carbon.

Salts of the compounds of the formula I may be prepared by generallyknown processes such as e.g. by reacting the compounds of the formula Iwith a corresponding base or acid in an appropriate solvent or solventmixture e.g. ethers (diethylether) or alcohols (ethanol, propanol orisopropanol).

Another object of the present invention concerns the use of the presentcompounds in the therapy of inflammatory diseases and conditions,especially of all diseases and conditions induced by excessive TNF-α andIL-1 secretion.

The inhibitors of production of cytokins or inflammation mediators,which are the object of the present invention, or pharmacologicallyacceptable salts thereof may be used in the production of drugs for thetreatment and prophylaxis of any pathological condition or diseaseinduced by excessive unregulated production of cytokins or inflammationmediators, which drugs should contain an effective dose of saidinhibitors.

The present invention specifically relates to an effective dose of TNF-αinhibitor, which may be determined by usual methods.

Further, the present invention relates to a pharmaceutical formulationcontaining an effective non-toxic dosis of the present compounds as wellas pharmaceutically acceptable carriers or solvents.

The preparation of pharmaceutical formulations may include blending,granulating, tabletting and dissolving ingredients. Chemical carriersmay be solid or liquid. Solid carriers may be lactose, sucrose, talcum,gelatine, agar, pectin, magnesium stearate, fatty acids etc. Liquidcarriers may be syrups, oils such as olive oil, sunflower oil or soyabean oil, water etc. Similarly, the carrier may also contain a componentfor a sustained release of the active component such as e.g. glycerylmonostearate or glyceryl distearate. Various forms of pharmaceuticalformulations may be used. Thus, if a solid carrier is used, these formsmay be tablets, hard gelatine capsules, powder or granules that may beadministered in capsules per os. The amount of the solid carrier mayvary, but it is mainly from 25 mg to 1 g. If a liquid carrier is used,the formulation would be in the form of a syrup, emulsion, soft gelatinecapsules, sterile injectable liquids such as ampoules or non-aqueousliquid suspensions.

Compounds according to the present invention may be applied perorally,parenterally, locally, intranasally, intrarectally and intravaginally.The parenteral route herein means intravenous, intramuscular andsubcutaneous applications. Appropriate formulations of the presentcompounds may be used in the prophylaxis as well as in the treatment ofvarious diseases and pathological inflammatory conditions induced by anexcessive unregulated production of cytokins or inflammation mediators,primarily TNF-α. They comprise rheumatoid arthritis, rheumatoidspondylitis, osteoarthritis and other arthritic pathological conditionsand diseases, eczemas, psoriasis and other inflammatory skin conditionssuch as burns induced by UV radiation (sun rays and similar UV sources),inflammatory eye diseases, Crohn's disease, ulcerative colitis andasthma.

The inhibitory action of the present compounds upon TNF-α and IL-1secretion was determined by the following in vitro and in vivoexperiments:

Determination of TNF-α and IL-1 Secretion in Human Peripheral BloodMononuclear Cells in vitro

Human peripheral blood mononuclear cells (PBMC) were prepared fromheparinized whole blood after separating PBMC on Ficoll-Paque ™Plus(Amersham-Pharmacia). To determine the TNF-α level, 3.5-5×10⁴ cells werecultivated in a total volume of 200 μl for 18 to 24 hours on microtitreplates with a flat bottom (96 wells, Falcon) in RPMI 1640 medium, intowhich there were added 10% FBS (Fetal Bovine Serum, Biowhittaker)previously inactivated at 54° C./30 min, 100 units/ml of penicillin, 100mg/ml of streptomycin and 20 mM HEPES (GIBCO). The cells were incubatedat 37° C. in an atmosphere with 5% CO₂ and 90% humidity. In a negativecontrol the cells were cultivated only in the medium (NC), whereas in apositive control TNF-α secretion was triggered by adding 1 ng/ml oflipopolysaccharides (LPS, E. coli serotype 0111:B4, SIGMA) (PC). Theeffect of the tested substances upon TNF-α secretion was investigatedafter adding them into cultures of cells stimulated by LPS (TS). TheTNF-α level in the cell supernatant was determined by ELISA procedureaccording to the suggestions of the producer (R&D Systems). The testsensitivity was <3 pg/ml TNF-α. The IL-1 level was determined in anassay under the same conditions and with the same number of cells andthe same concentration of stimuli stimulus by ELISA procedure (R&DSystems). The percentage of inhibition of TNF-α or IL-1 production wascalculated by the equation:% inhibition=[1−(TS−NC)/(PC−NC)]*100.

The IC₅₀ value was defined as the substance concentration, at which 50%of TNF-α production were inhibited.

Compounds showing IC₅₀ with 20 μM or lower concentrations are active.

Determination of TNF-α and IL-1 Secretion in Mouse PeritonealMacrophages in vitro

In order to obtain peritoneal macrophages, Balb/C mouse strain males,age 8 to 12 weeks, were injected i.p. with 300 μg of zymosan (SIGMA)dissolved in a phosphate buffer (PBS) in a total volume of 0.1 ml/mouse.After 24 hours the mice were euthanized according to the LaboratoryAnimal Welfare Act. The peritoneal cavity was washed with a sterilephysiological solution (5 ml). The obtained peritoneal macrophages werewashed twice with a sterile physiological solution and, after the lastcentrifugation (350 g/10 min), resuspended in RPMI 1640, into which 10%of FBS portion were added. In order to determine TNF-α secretion, 5×10⁴cells/well were cultivated in a total volume of 200 μl for 18 to 24hours on microtitre plates with a flat bottom (96 wells, Falcon) in RPMI1640 medium, into which 10% FBS (Fetal Bovine Serum, Biowhittaker)inactivated by heat, 100 units/ml of penicillin, 100 mg/ml ofstreptomycin, 20 mM HEPES and 50 μM 2-mercaptoethanol (all of GIBCO)were added. The cells were incubated at 37° C. in an atmosphere with 5%CO₂ and 90% humidity. In a negative control the cells were cultivatedonly in a medium (NC), whereas in a positive control the TNF-α secretionwas triggered by adding 10 ng/ml of lipopolysaccharides (LPS, E. coliserotype 0111 :B4, SIGMA) (PC). The effect of the substances upon theTNF-α secretion was investigated after adding them into cultures ofcells stimulated with LPS (TS). The TNF-α level in the cell supernatantwas determined by ELISA procedure (R&D Systems, Biosource). The IL-1level was determined in an assay identical to the assay for TNF-α byELISA procedure (R&D Systems). The percentage of inhibition of TNF-α orIL-1 production was calculated by the equation:% inhibition=[1−(TS−NC)/(PC−NC)]*100.

The IC₅₀ value was defined as the substance concentration, at which 50%of TNF-α production were inhibited.

Compounds showing IC₅₀ with 10 μM or lower concentrations are active.

In vivo Model of LPS-Induced Excessive TNF-α or IL-1 Secretion in Mice

TNF-α or IL-1 secretion in mice was induced according to the alreadydisclosed method (Badger AM et al., J. Pharmac. Env. Therap., 1996,279:1453-1461). Balb/C males, age 8 to 12 weeks, in groups of 6 to 10animals were used. The animals were treated p.o. either with a solventonly (in negative and in positive controls) or with solutions ofsubstances 30 minutes prior to i.p. treatment with LPS (E. coli serotype0111:B4, Sigma) in a dosis of 25 μg/animal. Two hours later the animalswere euthanized by means of i.p. Roumpun (Bayer) and Ketanest(Parke-Davis) injection. A blood sample of each animal was taken into aVacutainer tube (Becton Dickinson) and the plasma was separatedaccording to the producer's instructions. The TNF-α level in the plasmawas determined by ELISA procedure (Biosource, R&D Systems) according tothe producer's instructions. The test sensitivity was <3 pg/ml TNF-α.The IL-1 level was determined by ELISA procedure (R&D Systems). Thepercentage of inhibition of TNF-α or IL-1 production Was calculated bythe equation:% inhibition=[1−(TS−NC)/(PC−NC)]*100.

Active are the compounds showing 30% or more inhibition of TNF-αproduction at a dosis of 10 mg/kg.

Writhing Assay for Analgetic Activity

In this assay pain is induced by the injection of an irritant, mostfrequently acetic acid, into the peritoneal cavity of mice. Animalsreact with characteristic writhings, which has given the name of theassay (Collier H O J et al., Pharmac. Chemother., 1968, 32:295-310;Fukawa K et al., J. Pharmacol. Meth ., 1980, 4:251-259; Schweizer A etal., Agents Actions, 1988, 23:29-31). The assay is convenient for thedetermination of analgetic activity of compounds. Procedure: male Balb/Cmice (Charles River, Italy), age 8 to 12 weeks, were used. A controlgroup received methyl cellulose p.o. 30 minutes prior to i.p.application of acetic acid in a concentration of 0.6%, whereas testgroups received standard (acetylsalicylic acid) or test substances inmethyl cellulose p.o. 30 minutes prior to i.p. application of 0.6%acetic acid (volume 0.1 ml/10 g). The mice were placed individuallyunder glass funnels and the number of writhings was registered for 20minutes for each animal. The percentage of writhing inhibition wascalculated according to the equation:% inhibition=(mean value of number of writhings in the controlgroup−number of writhings in the test group)/number of writhings in thecontrol group*100.

Active are the compounds showing such analgetic activity asacetylsalicylic acid or better.

In vivo Model of LPS-Induced Shock in Mice

Male Balb/C mice (Charles River, Italy), age 8 to 12 weks, were used.LPS isolated from Serratie marcessans (Sigma, L-6136) was diluted insterile physiological solution. The first LPS injection was administeredintradermally in a dosis of 4 μg/mouse. 18 to 24 hours later, LPS wasadministered i.v. in a dosis of 200 μg/mouse. A control group receivedtwo LPS injections as disclosed above. The test groups receivedsubstances p.o. half an hour prior to each LPS application. Survivalafter 24 hours was observed.

Active are the substances at which the survival at a dosis of 30 mg/kgwas 40% or more.

Compounds from Example 14 show activity in at least two investigatedassays though these results only represent an illustration of thebiological activity of the compounds and should not limit the inventionin any way.

PREPARATION METHODS WITH EXAMPLES

The present invention is illustrated by the following Examples which arein no way a limitation thereof.

Example 1 8-Oxa-2-thia-dibenzo[e,h]azulene-1,3-dicarboxylic acidmonoethyl ester (1)

A solution of dibenzo[b,f]oxepin-10,11-dione (III; X═O, Y=Z=H) (0.004mole) and thioether (IV; R¹, R²=Et) (0.008 mole) in tert-butanol wasadded to a potassium butoxide solution (0.013 mole) in 5 ml oftert-butanol (10 ml), heated to 60° C. After 30 minutes of stirring at60° C., the reaction mixture was cooled and acidified with 5 M aqueousHCl solution (10 ml), whereupon the majority of the solvent wasevaporated at the temperature of 30° C. and the pressure of 30 hPa.Diethyl ether (20 ml) was added to the residue and then the solution wasextracted with 2 M NH₄OH solution (10 ml). The combined extracts wereacidified with diluted HCl to an acidic reaction and dicarboxylate inthe form of brown crystals was obtained.

Example 2 5-Chloro-8-oxa-2-thia-dibenzo[e,h]azulene-1,3-dicarboxylicacid 1-methyl ester (2)5-Chloro-8-oxa-2-thia-dibenzo[e,h]azulene-1,3-dicarboxylic acid 3-methylester (3)

According to the process of Example 1, starting from2-chloro-dibenzo[b,f]oxepin-10,11-dione (III; X═O, Y=2-Cl, Z=H) andthioether (IV; R¹, R²=Me), a mixture of dicarboxylates in the form of abrown oil was obtained.

Example 3 2,8-Dithia-dibenzo[e,h]azulene-1,3-dicarboxylic acid monoethylester (4)

According to the process of Example 1, starting fromdibenzo[b,f]tiepin-10,11-dione (III; X═S, Y=Z=H) and thioether (IV;R⁵=Et), dicarboxylate in the form of brown crystals was obtained.

Example 4 8-Oxa-2-thia-dibenzo[e,h]azulene-1-carboxylic acid ethyl ester(5) 8-Oxa-2-thia-dibenzo[e,h]azulene (9)

A homogenous mixture of dicarboxylate 1 (200 mg) and copper (150 mg) washeated for 2 hours at 300° C. After the cooling of the reaction mixture,diethyl ether was added thereto and the undissolved copper oxide wasfiltered off. The filtrate was evaporated under reduced pressure and theobtained product mixture was separated by chromatography on a column.Compounds 5 and 9 in crystal form were isolated.

Example 5 5-Chloro-8-oxa-2-thia-dibenzo[e,h]azulene-1-carboxylic acidmethyl ester (6) 11-Chloro-8-oxa-2-thia-dibenzo[e,h]azulene-1-carboxylicacid methyl ester (7) 5-Chloro-8-oxa-2-thia-dibenzo[e,h]azulene (10)

According to the process of Example 4, starting from a mixture ofdicarboxylates 2 and 3, a mixture of two monocarboxylates, 6 and 7, andof the compound 10 was obtained. The compound 10 was separated from themonocarboxylate mixture by chromatography on a column. Carboxylates 6and 7 were separated and determined by GC-MS as two close peaks withm/z=314 (MH⁺).

Example 6 2,8-Dithia-dibenzo[e,h]azulene-1-carboxylic acid ethyl ester(8) 2,8-Dithia-dibenzo[e,h]azulene (11)

According to the process of Example 4, starting from dicarboxylate 4there were prepared compounds 8 and 11. The mixture of the compounds wasseparated by chromatography on a column to give both products in crystalform.

Example 7 (8-Oxa-2-thia-dibenzo[e,h]azulene-1-yl)-methanol (12)

To a suspension of LiAlH₄ in dry ether (10 mmoles in 15 ml of dry ether)an ether solution of the ester 5 (2 mmoles in 15 ml of dry ether) wasadded drop by drop. The reaction mixture was stirred at room temperaturefor 4 hours. After the complete quantity of the ester had been reacted(the course of the reaction was followed by thin layer chromatography),the excess of LiAlH₄ was decomposed by the addition of diethyl ether andwater. The obtained white precipitate was filtered off and after dryingon anhydrous Na₂SO₄ the filtrate was evaporated under reduced pressure.The crude product was purified by chromatography on a column to give apure product in the form of yellowish crystals.

Example 8 (5-Chloro-8-oxa-2-thia-dibenzo[e,h]azulene-1-yl)-methanol (13)(11-Chloro-8-oxa-2-thia-dibenzo[e,h]azulene-1-yl)-methanol (14)

According to the process of Example 8, starting from the mixture ofesters 6 and 7 there was prepared a mixture of the title alcohols, whichwere separated by column chromatography to give pure substances in theform of yellowish crystals.

Example 9 (2,8-Dithia-dibenzo[e,h]azulene-1-yl)-methanol (15)

According to the process of Example 8, starting from the correspondingester 8 there was prepared an alcohol in the form of brown crystals.TABLE 1

Comp. X Y Z R² R¹ ¹H NMR (ppm) 1 O H H CO₂H CO₂Et 1.33 (t, 3H); 4.32 (m,2H); 7.14-7.19 (m, 2H); 7.31-7.42 (m, 7.54-7.64 (m, 2H) (CDCl₃) 2 O 5-ClH CO₂H CO₂Me 3 O H 11-Cl CO₂H CO₂Me 4 S H H CO₂H CO₂Et 1.15 (t, 3H);4.22 (m, 2H); 7.29-7.40 (m, 4H); 7.54-7.58 (m, 7.63-7.66 (m, 2H); 13.5(bs, 1H) (DMSO-d₆) 5 O H H H CO₂Et 1.32 (t, 3H); 4.33 (m, 2H); 7.17-7.67(m, 9H) (CDCl₃) 6 O 5-Cl H H CO₂Me 7 O H 11-Cl H CO₂Me 8 S H H H CO₂Et1.25 (t, 3H); 4.26 (m, 2H); 7.24-7.35 (m, 4H); 7.50-7.54 (m, 2H); 7.58(s, 1H); 7.62-7.67 (m, 2H) (CDCl₃) 9 O H H H H 7.24-7.30 (m, 2H);7.37-7.41 (m, 4H); 7.66-7.69 (m, 2H); 7.97 (s, 2H) (DMSO-d₆) 10 O 5-Cl HH H 7.19-7.58 (m, 9H) (CDCl₃) 11 S H H H H 7.25-7.37 (m, 4H); 7.49 (s,2H); 7.53-7.57 (m, 2H); 7.64-7.68 (m, 2H) (CDCl₃) 12 O H H H CH₂OH 1.76(bs, 1H); 4.97 (bd, 2H); 7.17-7.38 (m, 6H); 7.46 (s, 1H); 7.54-7.60 (m,2H) (CDCl₃) 13 O 5-Cl H H CH₂OH 4.88 (bs, 1H); 4.93 (s, 2H); 7.27-7.43(m, 5H); 7.67-7.70 (m, 2H); 7.80 (s, 1H) (CD₃COCD₃) 14 O H 11-Cl H CH₂OH4.93 (bs, 3H); 7.23-7.29 (m, 1H); 7.36-7.46 (m, 4H); 7.65-7.68 (m, 1H);7.73 (s, 1H); 7.82 (d, 1H) (CD₃COCD₃) 15 S H H H CH₂OH 1.84 (bs, 1H);4.13 (m, 2H); 7.23-7.38 (m, 4H); 7.40 (s, 1H), 7.48-7.50 (m, 2H);7.62-7.72 (m, 2H) (CDCl₃)

Example 10 a)Dimethyl-[3-(8-oxa-2-thia-dibenzo[e,h]azulene-1-ylmethoxy)-propyl]-amine

To a 3-dimethylaminopropylchloride-hydrochloride solution (2.5 mmoles)in 50% sodium hydroxide (3 ml), benzyltriethylammonium chloride (0.3mmole) and a toluene solution of the alcohol 12 (0.25 mmole) were added.The reaction mixture was heated under vigorous stirring and refluxingfor 4 hours. Then it was cooled to room temperature, diluted with waterand extracted with dichloromethane. After purification by columnchromatography an oily product was isolated.

¹H NMR (ppm, CDCl₃): 2.08 (m, 2H); 2.58 (s, 6H); 2.84 (m, 2H); 3.69 (m,2H); 4.75 (bd, 2H); 7.16-7.36 (m, 6H), 7.46 (s, 1H); 7.47-7.56 (m, 2H).

b)Dimethyl-[2-(8-oxa-2-thia-dibenzo[e,h]azulene-1-ylmethoxy)-ethyl]-amine

Starting from the alcohol 12 (0.25 mmole) and2-dimethylaminoethylchloride-hydrochloride (2.5 mmoles), an oily productwas obtained.

¹H NMR (ppm, CDCl₃): 2.52 (s, 6H); 2.86 (bs, 2H); 3.85 (bs, 2H); 4.80(bd, 2H); 7.16-7.36 (m, 6H); 7.46 (s, 1H); 7.49-7.56 (m, 2H).

c) 3-(8-Oxa-2-thia-dibenzo[e,h]azulene-1-ylmethoxy)-propylamine

Starting from the alcohol 12 (0.25 mmole) and3-chloropropylamine-hydrochloride (2.5 mmoles), an oily product wasobtained.

¹H NMR (ppm, CDCl₃): 1.99 (m, 2H); 3.05 (t, 2H); 3.70 (bs, 2H); 4.3-4.5(b, 2H); 4.72 (bs, 2H); 7.15-7.60 (m, 9H).

Example 11 a)3-(5-Chloro-8-oxa-2-thia-dibenzo[e,h]azulene-1-ylmethoxy)-propylamine

To a solution of 3-chloropropylamine-hydrochloride (2.2 mmoles) in 50%sodium hydroxide (3 ml), benzyltriethylammonium chloride (0.3 mmole) andtoluene solution of the alcohol 13 (0.22 mmole) were added. The reactionmixture was heated under vigorous stirring and refluxing for 5 hours.Then it was cooled to room temperature, diluted with water and extractedwith dichloromethane. After purification by column chromatography anoily product was isolated.

MS (m/z): 372 (MH⁺).

b)[2-(5-Chloro-8-oxa-2-thia-dibenzo[e,h]azulene-1-ylmethoxy)-ethyl]-dimethyl-amine

Starting from the alcohol 13 (0.29 mmole) and2-dimethylaminoethylchloride-hydrochloride (2.9 mmoles), an oily productwas obtained.

MS (m/z): 386 (NM⁺).

c)[3-(5-Chloro-8-oxa-2-thia-dibenzo[eh]azulene-1-ylmethoxy)-propyl]-dimethyl-amine

Starting from the alcohol 13 (0.22 mmole) and3-dimethylaminopropylchloride-hydrochloride (2.2 mmoles), an oilyproduct was obtained.

MS (m/z): 400 (MH⁺);

Example 12 a)[2-(11-Chloro-8-oxa-2-thia-dibenzo[e,h]azulene-1-ylmethoxy)-ethyl]-dimethyl-amine

To a solution of 2-dimethylaminoethylchloride-hydrochloride (1.8 mmoles)in 50% sodium hydroxide (3 ml), benzyltriethylammonium chloride (0.3mmole) and toluene solution of the alcohol 14 (0.18 mmole) were added.The reaction mixture was heated under vigorous stirring and refluxingfor 5 hours. Then it was cooled to room temperature, diluted with waterand extracted by dichloromethane. After purifiaction by columnchromatograpy an oily product was isolated.

MS (m/z): 386 (MH⁺).

b)3-(11-Chloro-8-oxa-2-thia-dibenzo[e,h]azulene-1-ylmethoxy)-propylamine

Starting from the alcohol 14 (0.18 mmole) and3-chloropropylamine-hydrochloride (1.8 mmoles), an oily product wasobtained.

¹H NMR (ppm, CD₃COCD₃): 1.82 (s, 2H); 1.97 (t, 2H); 3.36 (t, 2H); 3.76(bs, 2H); 4.74 (s, 2H); 7.26-7.82 (m, 8H);

MS (m/z): 372 (MH⁺).

Example 13 a)[3-(2,8-Dithia-dibenzo[e,h]azulene-1-ylmethoxy)-propyl]-dimethyl-amine

To a solution of 3-dimethylaminopropylchloride-hydrochloride (6.7mmoles) in 50% sodium hydroxide (5 ml), benzyltriethylammonium chloride(0.88 mmole) and toluene solution of the alcohol 15 (0.67 mmole) wereadded. The reaction mixture was heated under vigorous stirring andrefluxing for 5 hours. Then it was cooled to room temperature, dilutedwith water and extracted by dichloromethane. After purification bycolumn chromatograpy an oily product was isolated.

¹H NMR (ppm, CDCl₃): 2.04 (p, 2H); 2.57 (s, 6H); 2.82 (bs, 2H); 3.61 (m,2H); 4.67 (m, 2H); 7.27-7.71 (m, 8H); 7.40 (s, 1H).

b) [2-(2,8-Dithia-dibenzo[e,h]azulene-1-ylmethoxy)-ethyl]-dimethyl-amine

Starting from the alcohol 15 (0.67 mmole) and2-dimethylaminoethylchloride-hydrochloride (6.7 mmoles), an oily productwas obtained;

¹H NMR (ppm, CDCl₃): 2.49 (s, 6H); 2.86 (bs, 2H); 3.78 (m, 2H); 4.72 (m,2H); 7.23-7.70 (m, 8H); 7.40 (s, 1H).

c) 3-(2,8-Dithia-dibenzo[e,h]azulene-1-ylmethoxy)-propylamine

Starting from the alcohol 15 (0.27 mmole) and3-chloropropylamine-hydrochloride (2.7 mmoles), an oily product wasobtained.

MS (m/z): 354 (MH⁺).

Example 14 2,8-Dithia-dibenzo[e,h]azulene-1-carbaldehyde

To a dichloromethane solution of the alcohol 15 (3.0 mmoles in 40 ml)dipyridine-chromium-(VI)-oxide (pyridinyl dichromate, PDC, 0.006 mole)was added. The reaction mixture was stirred at room temperature for 18hours. Diethyl ether (50 ml) was added to the reaction mixture and thethus diluted reaction mixture was purified on a Florisil column to givea yellow crystal product.

¹H NMR (ppm, CDCl₃): 7.29-7.45 (m, 5H); 7.53-7.56 (m, 1H); 7.65-7.68 (m,1H); 7.72-7.75 (m, 1H); 7.81 (d, 1H); 9.84 (s, 1H).

1. A compound of the formula I

characterized in that X may be CH₂ or a hetero atom such as O, S, S(═O),S(═O)₂, or NR^(a), wherein R^(a) is hydrogen or a protecting group; Yand Z independently from each other denote one or more identical ordifferent substituents linked to any available carbon atom, and may behydrogen, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkinyl,trifluoromethyl, halo-C₁-C₄ alkyl, hydroxy, C₁-C₄ alkoxy,trifluoromethoxy, C₁-C₄ alkanoyl, amino, amino-C₁-C₄ alkyl, C₁-C₄alkylamino, N—(C₁-C₄-alkyl)amino, N,N-di(C₁-C₄-alkyl)amino, thiol, C₁-C₄alkylthio, sulfonyl, C₁-C₄ alkylsulfonyl, sulfinyl, C₁-C₄ alkylsulfinyl,carboxy, C₁-C₄ alkoxycarbonyl, cyano, nitro; R¹ may be hydrogen,halogen, C₁-C₇ alkyl optionally substituted with one, two, three or moresubstituents selected from the group comprising halogen atom, hydroxy,C₁-C₄ alkoxy, thiol, C₁-C₄ alkylthio, amino, N—(C₁-C₄) alkylamino,N,N-di(C₁-C₄-alkyl)-amino, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl;C₂-C₇ alkenyl optionally substituted with one, two, three or morehalogen atoms; C₂-C₇ alkinyl, monocyclic or bicyclic aryl group havingfrom 6 to 10 carbon atoms and with alternating double bonds and whichgroup can be optionally substituted with one or two substituentsselected from the group comprising fluoro, chloro, C₁-C₄ alkyl cyano,nitro, hydroxy, C₁-C₄ alkoxy, thiol, C₁-C₄ alkylthio, amino, N—(C₁-C₄)alkylarnino, N,N-di(C₁-C₄-alkyl)-amino, sulfonyl, C₁-C₄ alylsulfonyl,sulfinyl, C₁-C₄ alkylsulfinyl and can be linked to the rest of themolecule by any available carbon atom via direct bond or via C₁-C₄alkylene group; monocyclic or bicyclic heteroaryl having the meaning ofaromatic and partially aromatic groups of a monocyclic or bicyclic ringwith 4 to 12 carbon atoms and at least one of them being heteroatomselected from the group consisting of O, S, N, wherein available carbonor nitrogen represent the binding site of the group to the rest of themolecule either via direct bond or via C₁-C₄ alkylene group and wheresaid heteroaryl can be optionally substituted with fluoro, chloro, C₁-C₄alkyl, cyano, nitro, hydroxy, C₁-C₄ alkoxy, thiol, C₁-C₄ alkylthio,amino, N—(C₁-C₄) alkylamino, N,N-di(C₁-C₄-alkyl)-amino, sulfonyl, C₁-C₄alkylsulfonyl, sulfinyl, C₁-C₄ alkylsulfinyl; five-member or six-memberfully saturated or partly unsaturated heterocycle groups containing atleast one hetero atom selected from the group consisting of O, S or N,wherein carbon or nitrogen represent the binding site of the group tothe rest of the molecule either via direct bond or via C₁-C₄ alkylenegroup and where said heteroaryl can be optionally substituted withfluoro, chloro, C₁-C₄ alkyl, cyano, nitro, hydroxy, C₁-C₄ alkoxy, thiol,C₁-C₄ alkylthio, amino, N—(C₁-C₄) alkylamino, N,N-di(C₁-C₄-alkyl)-amino,sulfonyl, C₁-C₄ alkylsulfonyl, sulfinyl, C₁-C₄ alkylsulfinyl; hydroxy,hydroxy-C₂-C₇ alkenyl, hydroxy-C₂-C₇ alkinyl, C₁-C₇ alkoxy, thiol,thio-C₂-C₇ alkenyl, thio-C₂-C₇ alkinyl, C₁-C₇ alkylthio, amino, N—(C₁-C₇alkyl)amino, N,N-di-(C₁-C₇ alkyl)amino, C₁-C₇ alkylamino, amino-C₂-C₇alkenyl, amino-C₂-C₇ alkinyl, amino-C₁-C₇ alkoxy, C₁-C₇ alkanoyl, aroyl,oxo-C₁-C₇ alkyl, C₁-C₇ alkanoyloxy, carboxy, C₁-C₇ alkyloxycarbonyl oraryloxycarbonyl, carbamoyl, N—(C₁-C₇-alkyl)carbamoyl,N,N-di(C₁-C₇-alkyl)carbamoyl, cyano, cyano-C₁-C₇ alkyl, sulfonyl, C₁-C₇alkylsulfonyl, sulfinyl, C₁-C₇ alkylsulfinyl, nitro, or a substituent ofthe formula II

wherein R³ and R⁴ simultaneously or independently from each other may behydrogen, C₁-C₄ alkyl, aryl or together with N have the meaning ofheterocycle or heteroaryl selected from the group consisting ofmorpholine-4-yl, piperidine-1-yl, pyrrolidine-1-yl, imidazole-1-yl orpiperazine-1-yl; m and n represent an integer from 0 to 3; Q₁ and Q₂represent, independently from each other, oxygen, sulfur or groups:

wherein the substituents y₁ and y₂ independently from each other may behydrogen, halogen, an optionally substituted C₁-C₄ alkyl or aryl,wherein the optionally substituted alkyl or aryl have the meanings asdefined above, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkanoyl, thiol, C₁-C₄alkylthio, sulfonyl, C₁-C₄ alkylsulfonyl, sulfinyl, C₁-C₄ alkylsulfinyl,cyano, nitro or together form carbonyl or imino group; R² may behydrogen, carboxy or alkyloxycarbonyl; as well as pharmacologicallyacceptable salts and solvates thereof.
 2. A compound according to claim1, characterized in that X represents S or O.
 3. A compound according toclaim 2, characterized in that Y and/or Z represent H or Cl.
 4. Acompound and a salt according to claim 3, characterized in that R¹and/or R² represent H, Br, COOH, COOMe, COOEt.
 5. A compound accordingto claim 3, characterized in that R¹ represents H and R² representsCOOMe, COOEt, CHO, CH₂OH.
 6. A compound and a salt according to claim 3,characterized in that R¹ represents H and R² has the meaning of formulaII.
 7. A compound and a salt according to claim 6, characterized in thatm has the meaning of 1 and the symbol n has the meaning of 1 or 2, Q₁represents O and Q₂ represents CH₂.
 8. A compound and a salt accordingto claim 7, characterized in that R³ and R⁴ represent H or Me. 9.Selected compounds according to claim 4:8-oxa-2-thia-dibenzo[e,h]azulene; 2,8-dithia-dibenzo[e,h]azulene;5-chloro-8-oxa-2-thia-dibenzo[e,h]azulene;8-oxa-2-thia-dibenzo[e,h]azulene-1,3-dicarboxylic acid monoethyl ester;5-chloro-8-oxa-2-thia-dibenzo[e,h]azulene-1,3-dicarboxylic acid 1-methylester; 5-chloro-8-oxa-2-thia-dibenzo[e,h]azulene-1,3-dicarboxylic acid3-methyl ester; 2,8-dithia-dibenzo[e,h]azulene-1,3-dicarboxylic acidmonoethyl ester.
 10. Selected compounds according to claim 5:8-oxa-2-thia-dibenzo[e,h]azulene-1-carboxylic acid ethyl ester;5-chloro-8-oxa-2-thia-dibenzo[e,h]azulene-1-carboxylic acid methylester; 11-chloro-8-oxa-2-thia-dibenzo[e,h]azulene-1-carboxylic acidmethyl ester; 2,8-dithia-dibenzo[e,h]azulene-1-carboxylic acid ethylester; 2,8-dithia-dibenzo[e,h]azulene-1-carbaldehyde;(8-oxa-2-thia-dibenzo[e,h]azulene-1-yl)-methanol;(5-chloro-8-oxa-2-thia-dibenzo[e,h]azulene-1-yl)-methanol;(11-chloro-8-oxa-2-thia-dibenzo[e,h]azulene-1-yl)-methanol;(2,8-dithia-dibenzo[e,h]azulene-1-yl)-methanol.
 11. Selected compoundsand salts according to claim 8:dimethyl-[3-(8-oxa-2-thia-dibenzo[e,h]azulene-1-ylmethoxy)-propyl]-amine;dimethyl-[2-(8-oxa-2-thia-dibenzo[e,h]azulene-1-ylmethoxy)-ethyl]-amine;3-(8-oxa-2-thia-dibenzo[e,h]azulene-1-ylmethoxy)-propylamine;3-(5-chloro-8-oxa-2-thia-dibenzo[e,h]azulene-1-ylmethoxy)-propylamine;[2-(5-chloro-8-oxa-2-thia-dibenzo[e,h]azulene-1-ylmethoxy)-ethyl]-dimethyl-amine;[3-(5-chloro-8-oxa-2-thia-dibenzo[e,h]azulene-1-ylmethoxy)-propyl]-dimethyl-amine;[2-(11-chloro-8-oxa-2-thia-dibenzo[e,h]azulene-1-ylmethoxy)-ethyl]-dimethyl-amine;3-(11-chloro-8-oxa-2-thia-dibenzo[e,h]azulene-1-ylmethoxy)-propylamine;[3-(2,8-dithia-dibenzo[e,h]azulene-1-ylmethoxy)-propyl]-dimethyl-amine;[2-(2,8-dithia-dibenzo[e,h]azulene-1-ylmethoxy)-ethyl]-dimethyl-amine;3-(2,8-dithia-dibenzo[e,h]azulene-1-ylmethoxy)-propylamine.
 12. Aprocess for the preparation of the compounds of the formula I:

characterized in that X may be CH₂ or a hetero atom such as O, S, S(═O),S(═O)₂, or NR^(a), wherein R^(a) is hydrogen or a protecting group; Yand Z independently from each other denote one or more identical ordifferent substituents linked to any available carbon atom, and may behydrogen, halogen, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄ alkinyl,trifluoromethyl, halo-C₁-C₄ alkyl, hydroxy, C₁-C₄ alkoxy,trifluoromethoxy, C₁-C₄ alkanoyl, amino, amino-C₁-C₄ alkyl, C₁-C₄alkylamino, N—(C₁-C₄-alkyl)amino, N,N-di(C₁-C₄-alkyl)amino, thiol, C₁-C₄alkylthio, sulfonyl, C₁-C₄ alkylsulfonyl, sulfinyl, C₁-C₄ alkylsulfinyl,carboxy, C₁-C₄ alkoxycarbonyl, cyano, nitro; R¹ may be hydrogen,halogen, C₁-C₇ alkyl optionally substituted with one, two, three or moresubstituents selected from the group comprising halogen atom, hydroxy,C₁-C₄ alkoxy, thiol, C₁-C₄ alkylthio, amino, N—(C₁-C₄) alkylamino,N,N-di(C₁-C₄-alkyl)-amino, C₁-C₄ alkylsulfonyl, C₁-C₄ alkylsulfinyl;C₂-C₇ alkenyl optionally substituted with one, two, three or morehalogen atoms; C₂-C₇ alkinyl, monocyclic or bicyclic aryl group havingfrom 6 to 10 carbon atoms and with alternating double bonds and whichgroup can be optionally substituted with one or two substituentsselected from the group comprising fluoro, chloro, C₁-C₄ alkyl, cyano,nitro, hydroxy, C₁-C₄ alkoxy, thiol, C₁-C₄ alkylthio, amino,N—(C₁-C₄)alkylamino, N,N-di(C₁-C₄-alkyl)-amino, sulfonyl, C₁-C₄alkylsulfonyl, sulfinyl, C₁-C₄ alkylsulfinyl and can be linked to therest of the molecule by any available carbon atom via direct bond or viaC₁-C₄ alkylene group; monocyclic or bicyclic heteroaryl having themeaning of aromatic and partially aromatic groups of a monocyclic orbicyclic ring with 4 to 12 carbon atoms and at least one of them beingheteroatom selected from the group consisting of O, S, N whereinavailable carbon or nitrogen represent the binding site of the group tothe rest of the molecule either via direct bond or via C₁-C₄ alkylenegroup and where said heteroaryl can be optionally substituted withfluoro, chloro, C₁-C₄ alkyl, cyano, nitro, hydroxy, C₁-C₄ alkoxy, thiol,C₁-C₄ alkylthio, amino, N—(C₁-C₄)alkylamino, N,N-di(C₁-C₄-alkyl)-amino,sulfonyl, C₁-C₄ alkylsulfonyl, sulfinyl, C₁-C₄ alkylsulfinyl;five-member or six-member fully saturated or partly unsaturatedheterocycle groups containing at least one hetero atom selected from thegroup consisting of O, S or N, wherein carbon or nitrogen represent thebinding site of the group to the rest of the molecule either via directbond or via C₁-C₄ alkylene group and where said heteroaryl can beoptionally substituted with fluoro, chloro, C₁-C₄ alkyl, cyano, nitro,hydroxy, C₁-C₄ alkoxy, thiol, C₁-C₄ alkylthio, amino,N—(C₁-C₄)alkylamino, N,N-di(C₁-C₄-alkyl)-amino, sulfonyl, C₁-C₄alkylsulfonyl, sulfinyl, C₁-C₄ alkylsulfinyl;hydroxy, hydroky-C₂-C₇alkenyl, hydroxy-C₂-C₇ alkinyl, C₁-C₇ alkoxy, thiol, thio-C₂-C₇ alkenyl,thio-C₂-C₇ alkinyl, C₁-C₇ alkylthio, amino, N—(C₁-C₇ alkyl)amnino,N,N-di-(C₁-C₇ alkyl)amino, C₁-C₇ alkylamino, amino-C₂-C₇ alkenyl,amino-C₂-C₇ alkinyl, amino-C₁-C₇ alkoxy, C₁-C₇ alkanoyl, aroyl,oxo-C₁-C₇ alkyl, C₁-C₇ alkanoyloxy, carboxy, C₁-C₇ alkyloxycarbonyl oraryloxycarbonyl, carbamoyl, N—(C₁-C₇-alkyl)carbamoyl,N,N-di(C₁-C₇-alkyl)carbamoyl, cyano, cyano-C₁-C₇ alkyl, sulfonyl, C₁-C₇alkylsulfonyl, sulfinyl, C₁-C₇ alkylsulfinyl, nitro, or a substituent ofthe formula II

wherein R³ and R⁴ simultaneously or independently from each other may behydrogen, C₁-C₄ alkyl, aryl or together with N have the meaning ofheterocycle or heteroaryl selected from the group consisting ofmorpholine-4-yl, piperidine-1-yl, pyrrolidine-1-yl, imidazole-1 -yl orpiperazine-1-yl; m and n represent an integer from 0 to 3; Q₁ and Q₂represent, independently from each other, oxygen, sulfur or groups:

wherein the substituents y₁ and y₂ independently from each other may behydrogen, halogen, an optionally substituted C₁-C₄ alkyl or aryl whereinthe optionally substituted alkyl or aryl have the meanings as definedabove, hydroxy, C₁-C₄ alkoxy, C₁-C₄ alkanoyl, thiol, C₁-C₄ alkylthio,sulfonyl, C₁-C₄ alkylsulfonyl, sulfinyl, C₁-C₄ alkylsulfinyl, cyano,nitro or together form carbonyl or imino group; R² may be hydrogen,carboxy or alkyloxycarbonyl; as well as pharmacologically acceptablesalts and solvates thereof, characterized in that the processess for thepreparation comprise: a) for the compounds of the formula I, wherein R¹and R² represent, independently from each other, carboxyl group, C₁-C₆alkyloxycarbonyl, aryloxycarbonyl or arylalkyloxycarbonyl, a cyclisationof α-diketones of the formula III:

with compounds of the formula IV:

b) for the compounds of the formula I, wherein Q₁ has the meaning of—O—, a reaction of alcohols of the formula V:

with compounds of the formula VI:

wherein R⁵ has a meaning of a leaving group; c) for the compounds of theformula I, wherein Q₁ has the meaning of —O—, —NH—, —S—or —C≡C—, areaction of the compounds of the formula Va:

wherein L¹ has the meaning of a leaving group with compounds of theformula VIa:

d) for the compounds of the formula I, wherein Q₁ has the meaning of—O—, —NH— or —S—, a reaction of the compounds of the formula Vb:

with the compounds of the formula VI, wherein R⁵ has the meaning of aleaving group; e) for the compounds of the formula I, wherein Q₁ has themeaning of —C═C—, a reaction of the compounds of the formula Vb, whereinQ₁ has the meaning of carbonyl, with phosphorous ylides.
 13. Use ofcompounds of the formula I according to claim 4 as intermediates for thepreparation of novel compounds of 2-thia-dibenzoazulene class withantiinflammatory action.
 14. Use of compounds of the formula I accordingto claim 6 as inhibitors of production of cytokins or inflammationmediators for the treatment and prophylaxis of any pathologicalconditions or diseases induced by excessive unregulated production ofcytokins or inflammation mediators by administering a nontoxic dosis ofsuitable pharmaceutical preparations perorally, parenterally or locally.15. Use of compounds of the formula I according to claim 5 asintermediates for the preparation of novel compounds of2-thia-dibenzoazulene class with antiinflammatory action.